Thrombotic complications are a major cause of death in the industrialized world. Examples of these complications include acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura. Thrombotic and restenotic complications also occur following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and prostheses. It is generally thought that platelet aggregates play a critical role in these events. Blood platelets, which normally circulate freely in the vasculature, become activated and aggregate to form a thrombus with disturbed blood flow caused by ruptured atherosclerotic lesions or by invasive treatments such as angioplasty, resulting in vascular occlusion.
An important mediator of platelet activation and aggregation is ADP (adenosine 5′-diphosphate) which is released from blood platelets in the vasculature upon activation by various agents, such as collagen and thrombin, and from damaged blood cells, endothelium or tissues. Activation of ADP results in the recruitment of more platelets and stabilization of existing platelet aggregates. Adenosine nucleotides that are released following platelet activation signal through the P2 purinergic receptors on the platelet membrane (Mills, D. C. Thromb. Haemost. 1996, 76:835-56; Gachet, C. Annu Rev Pharmacol Toxicol 2006, 46:277-300). P2 receptors are classified as either ligand-gated ion channels (P2X) or G-protein coupled receptors (GPCRs) designated as P2Y receptors (Abbrachio, M. P., Burnstock, G. Pharmacol Ther 1994, 64:445-75). Although initially thought to mediate its effects through a single receptor (termed P2YADP (Fredholm, B. B. et al, TIPS 1997, 18:79-82), ADP has more recently been shown to act on platelets through two GPCRs, the Gq-coupled P2Y1 receptor, and the Gi-coupled P2Y12 receptor. The P2Y12 receptor was identified through expression cloning (Hollopter, G. et al, Nature 2001, 409:202-07), and has been demonstrated to play a critical role in thrombus stability (Andre, P. et al, J Clin Inves, 2003, 112:398-406) and is the target of the thienopyridine drugs ticlopine and clopidogrel. ATP, on the other hand, acts through the ligand-gated channel P2X1 on platelets (Gachet, C. Annu Rev Pharmacol Toxicol 2006, 46:277-300).
U.S. Patent Publication US 2007/0123547, titled “[4-(6-Halo-7-substituted-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureas And Forms And Methods Related Thereto,” filed Nov. 3, 2006, the contents of which are incorporated herein by reference in its entirety, discloses a platelet ADP receptor inhibitor compound, [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, (Compound A), which has the following structure:
and acts as a specific antagonist of P2Y12.
Since treatment for diseases such as acute coronary syndrome might require coadministration of an antiplatelet agent and an anticoagulant agent, a combination would allow for increased efficacy and may provide an improved safety profile. Thus, there is a need for combination therapies combining an antiplatelet agent with an anticoagulant agent that have enhanced efficacy. There is also a need for a combination therapy that allows for lower (i.e. sub-therapeutic) dosages of each individual agent to be used in the combination which may provide an improved safety profile.
There is also a need for combination of two different antiplatelet drugs that act by different mechanisms (e.g., a P2Y12 antagonist (Compound A) and a cox-1 inhibitor (aspirin)) in combination with an anticoagulant, as such a triple combination (clopidogrel, aspirin and heparin) is presently used in the clinic (as separate entities) during angioplasty procedures and has been found to be more efficatious than any of these drugs used alone or a combination of any two of these agents.